During the past 12 months work has been continued on gamma-(N)- formylheterocyclic thiosemicarbazones. The major problem being attacked is to retain high antitumor activity while improving pharmacological properties, specifically solubility and metabolic durability. These compounds are the most potent known inhibitors of mammalian tumor- derived ribonucleoside diphosphate reductase (RDR). The correlation of structure-activity relations in-vitro (collaboration with Dr. R.W. Brockman, Southern Research Institute) has been completed and an in- vitro-in-vivo correlation is approaching completion on approximately 100 compounds, mostly pyridine and isoquinoline derivatives. The lessons learned are very complex. Major effort has been devoted to developing synthetic methods for the indicated new structural types. Most standard syntheses are inapplicable and frequently 5-15 steps are required. These drugs do act, in part at least, by forming enzyme-iron-drug complexes with RDR. Efforts are being made to formulate a working picture of this enzyme, as yet impure and of unknown structure. We are attempting various graphic methods to shed light on this problem. We have donated approximately 100 compounds to another group for pertinent antiviral studies. The results are very unusual and should be published soon. Within the limits of our resources we are attempting to develop additional types of ligand and non-ligand drugs. Much of this work is dependent on close collaboration with the New Drug Development Branch of the National Cancer Institute.